I. Introduction
This invention relates to wetting the surface of the eye and/or an ocular prosthesis, providing mechanical lubrication therefor, reducing the evaporation of fluid from the surface of the eye and delivering a medicament to the ocular surface. In a preferred embodiment of the invention, the invention relates to an ophthalmic composition for dry eye treatment.
II. Description of the Prior Art
It is known that an aqueous tear film extends over the ocular surfaces and maintains the ocular surface moist and lubricated. It is also known that dehydration of moisture from the eye may result in discomfort. Further, it is known that compositions are available in the market intended for dry eye treatment. These compositions are primarily aqueous materials that supplement the tear film.
The most common treatment for dry eye involves temporary alleviation of dry eye symptoms by topical application of a tear substitute that adds a large volume of liquid to the anterior surface of the eye and related adnexa. Typical tear substitute compositions comprise water soluble polymer solutions. Examples of such solutions include saline solutions of polyvinyl alcohol, hydroxypropylmethyl cellulose or carboxymethyl celluloses. U.S. Pat. No. 4,421,748 teaches an artificial tear composition comprising an aqueous hypotonic solution of lecithin and a viscosity adjusting agent such as a solution soluble cellulose.
Methods used to quantify the effectiveness of tear substitutes for dry eye treatment solutions have not been standardized, and many methods used to quantify the results obtained using such tear substitute compositions are often inaccurate. For this reason, it is known that reported relief of dry eye symptoms using known tear substitutes varies considerably from subject to subject, and regardless of the method used to quantify relief using a tear substitute, relief often does not exceed several minutes.
The symptoms associated with dry eye are often exacerbated with subjects using ocular prostheses such as contact lenses. In some cases, contact lens intolerance is caused by the condition of dry eye and its symptoms. Further, the rate of evaporation from the eye is accelerated by the nature of the contact lens surface, and the physical presence of the contact lens results in menisci formation with additional physical and evaporative effects, even with subjects having an adequate tear film. For many subjects, contact lens intolerance is not overcome by topical application of tear substitutes. Therefore, there is a continuing need for improved compositions and processes for treatment of the dry eye condition and for improving tolerance to ocular prostheses.
An improved composition for dry eye treatment is the subject of U.S. Pat. No. 4,914,088 incorporated herein by reference. This patent teaches the use of charged phospholipids for the treatment of dry eye symptoms. In accordance with the patent, a phospholipid composition, preferably in the form of an aqueous emulsion, is topically applied to the eye where it is believed to disperse over the ocular surface and form a film that replicates a lipid layer formed by spreading a naturally occurring lipid secreted principally from the Meibomian glands during blinking. Because the phospholipid, when applied to the eye, carries a net charge, it is believed that aligned molecules repel each other preventing complex aggregate formation thereby resulting in a stable phospholipid film.
In copending U.S. patent applications Ser. Nos. 07/529,657 and 07/638,215, filed respectively May 29, 1990 and Jan. 7, 1991, assigned to the same assignee as the subject application (hereafter the "copending applications") and incorporated herein by reference, further improvements in dry eye treatment are disclosed. In accordance with the disclosures of the copending applications, the dry eye treatment composition of U.S. Pat. No. 4,914,088 is improved by use of an essentially non-polar oil as a component of a dry eye treatment composition. The oil increases the longevity of the tear film formed on the eye following addition of the dry eye treatment solution, presumably by providing and/or thickening the dehydration barrier (the layer) on the outer surface of the tear film. Thus, the oil increases the efficacy of the dry eye treatment solution and reduces performance variability from subject to subject. In addition, it is a further discovery of the copending applications that for many patients, the use of oil alone is efficacious in treatment of the dry eye condition.
The copending applications also teach the desirability of regulating the dosage of the oil applied to the eye. In accordance with the inventions disclosed in the copending applications, the total amount of oil available for formation of a film does not exceed that amount that would cause blurring and preferably does not exceed 25 ul. As the amount of oil exceeds a desired amount, the oil film formed over the eye becomes excessively thick or, alternatively, oil globules may form on the surface of the eye and not spread evenly over the eye. In either case, a thick oil layer is likely to contribute to patient blurring. The amount of oil beyond which blurring will occur varies from patient to patient and is dependent upon the specific oil used.
To understand how the treatment compositions of the above cited patent and copending applications function, and how the compositions disclosed herein function, the mechanism by which a barrier film over the eye is capable of alleviating dry eye symptoms should be understood.
It is reported that a naturally occurring tear film comprises a complex coating with three separate layers. The inner layer in contact with the ocular surface of the eye is said to be composed primarily of mucous, and renders the hydrophobic epithelial cell plasma membrane surface hydrophilic. The middle layer of the tear film is an aqueous layer. This layer is the thickest portion of the tear film, which is a source of moisture and lubrication for the eye and functions as an optical planarizing layer. The outer layer of the tear film, at the interface with the atmosphere, is a non-polar oily, naturally occurring lipid layer. This oily lipid layer is reported to act as a barrier that prevents evaporation of the aqueous layer (Mishima and Maurice: "The oily layer of the tear film and evaporation from the corneal surface," Exp. Eye Res. 1961; 1:39-45). Finally, the oily layer is bound to the aqueous layer through a polar interfacial lipid layer containing phospholipids.
The polar lipids which include the phospholipids, and the non-polar oily lipid components of the tear film are thought to originate primarily from secretions of the Meibomian glands. The oily layer of the tear film is formed from these secretions and is constantly replenished during blinking by expression of the secretions from the Meibomian glands and then spreading of the same over the surface of the eye by the eyelids. By constantly spreading the polar and non-polar lipids over the eye during blinking, the tear film is maintained and evaporation of the aqueous middle layer of the tear film is minimized.
A cause of dry eye is believed to be a deficiency in the quantity or quality of secretions from the Meibomian glands. It is postulated that a cause of dry eye is a deficiency in the polar lipid layer of the tear film, the non-polar oily lipid layer, or both. Regardless of the cause of the deficiency, the compromised lipid layer fails to act as an adequate barrier against evaporation of the aqueous portion of the tear film resulting in one form of the dry eye condition.
In accordance with the invention of U.S. Pat. No. 4,914,088, a charged phospholipid added to the eye is believed to disperse over the ocular surface to form a film replicating the lipid layer formed by spreading a naturally occurring lipid secreted from the Meibomian glands during blinking. Where the phospholipid applied to the eye carries a net charge, it is believed that the aligned molecules repel each other such that complex aggregate formation is prevented and the integrity of the phospholipid film is maintained.
The above-referenced copending applications involve adding a non-polar oil to the eye alone or in combination with the charged phospholipid, preferably in the form of an oil-in-water emulsion. Upon application of the treatment composition to the eye, it was postulated that the negatively charged phospholipid layer forms an aligned film over the aqueous tear film with charged ends dissolved in the aqueous layer and hydrophobic ends furthest removed from the aqueous layer available to bond with the non-polar oil layer. This causes the oil layer to disperse over the top surface of the eye as a thin, continuous and stable layer that functions as an evaporation barrier. Recognizing that the tear film naturally occurring in the eye may be deficient in the phospholipid component, the oil component, or both, the preferred embodiment of the treatment composition of said applications replenished both components of the tear film, thereby reducing variations in efficacy from patient to patient.
In the second of the copending applications, it is disclosed that to avoid blurred vision, the total amount of oil comprising the film over the ocular surface had to be controlled, the treatment composition is desirably added to the eye in the form of a meta-stable emulsion to enhance differentiation of the emulsion on the ocular surface, and the treatment composition desirably contains a surfactant that permits an increase in the oil content of an emulsion enabling rapid formation of a film of the efficacious components of the treatment composition over the ocular surface.
The use of the dry eye treatment of the referenced patent and copending applications assist in overcoming dry eye symptoms as reported therein. However, with time, the thick oil film formed using the compositions of the copending applications thins and dissipates and consequently, there is a continuing need to prolong the presence of the replicated tear film on the ocular surface beyond that disclosed in the copending applications.